关键词: 辛伐他汀, 辛伐他汀酸, 液相色谱-串联质谱, 血药浓度, 药代动力学

Abstract: AIM: To develop LC-MS /MS method for simultaneous determination of simvastatin and simvastatin acid concentrations in rat plasma, and investigate the pharmacokinetic effects of Wuzhi capsule (WZC) on simvastatin and simvastatin acid concentrations in rats.  METHODS: The method was based on simple liquid liquid extraction (LLE) with lovastatin as internal standard. Agilent Eclipse-C18 (2.1 mm×150 mm, 3.5 μm) was used as the chromatographic column, while water-acetonitrile (both of containing 0.1% formic acid) (5∶95, V/V) was used as the mobile phase. Detection was performed with multiple reactions monitoring (MRM) using electrospray ionization (ESI).Twelve male rats were divided into control group and experimental group, with 6 rats in each group. The control group was given 40 mg/kg simvastatin by gavage, and the experimental group was given 150 mg/kg Wuzhi capsule (containing deoxyschizandrin 11.25 mg per capsule) by gavage and followed by 40 mg/kg simvastatin by gavage after 15 minutes. About 0.5 mL of blood was collected from the orbital vein plexus of rats in heparin tube at the time points of 0.25, 0.5, 0.75, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 12.0 hours before and after administration, respectively. The relevant pharmacokinetic parameters were calculated by Phoenix software. RESULTS: The calibration curves of simvastatin and its metabolite simvastatin acid showed a good linearity over the concentration range of 5-5 000 ng/mL with the lower limit of quantitation of 5 ng/mL (simvastatin r=0.994 0, simvastatin acid r=0.994 54). The intra-day and inter-day relative standard deviations were both below 10%, and the absolute recovery could reach more than 80%.The major pharmacokinetic parameters were as follows (control group vs. experimental group), Cmax［(97±24) vs. (590±227) ng/mL, (385±137) vs. (1 322±502) ng/mL］, AUC0-t ［(446±70) vs. (1 315±535) ng·h·mL- 1, (1 305±531) vs. (3 393±1 047) ng·h·mL- 1)］, t1/2 ［(2.37±0.18) vs. (2.93±0.78) h, (2.39±0.43) vs. (3.44±0.80) h] increased significantly (P<0.05). CONCLUSION: The LC-MS/MS method established in this study is fast, simple, sensitive and specific, and is suitable for the determination of simvastatin and simvastatin acid in rat plasma. Wuzhi capsule could affect the pharmacokinetic parameters of simvastatin and simvastatin acid in rats. It is suggested that the combination of two drugs in clinical practice will cause significant interaction.

Key words: simvastatin, simvastatin acid, LC-MS/MS, blood concentration, pharmacokinetics